Miliary Tuberculosis

What is Miliary Tuberculosis?

Tuberculosis (TB), a disease caused by the bacteria called Mycobacterium tuberculosis (MTB), is typically spread from person to person. This happens when an infected person coughs, sneezes, or talks, releasing tiny droplets that contain the bacteria into the air. These droplets can linger in the air for a while and can be breathed in by other people. Notably, other ways of catching the bacteria are extremely rare.

While TB commonly affects the lungs, up to a third of all TB cases involve other organs. The bacteria tend to settle in the well-oxygenated areas of the lungs – the upper and the lower parts closest to the pleura, a membrane that lines the surface of the lungs.

Now, let’s talk a bit about the structure of the lungs: they are made up of alveoli, small air sacs which exchange gases between the lungs and the blood. Alveoli walls, or the “blood-air barrier”, allow gases to pass through smoothly. Inside these alveoli are cells called alveolar macrophages. These cells play a crucial role in keeping the lungs healthy, but they also play a part in the development of TB.

Let’s also consider how blood circulates in the lungs. Pulmonary arteries bring in deoxygenated blood into the lungs, while pulmonary veins carry oxygenated blood back to the heart. Bronchial arteries and veins are responsible for supplying and draining blood from the root of the lungs. The lymphatic system in the lungs, which carries lymph (a fluid with infection-fighting white blood cells), is also an important part of lung function.

In patients with a weakened immune system, the immune system may fail to contain the MTB infection, which can then spread from the lungs to other organs through the system of blood vessels. This is referred to as disseminated TB, which is when at least two separate organs of the body are infected, or if there is an infection in the blood, bone marrow, or liver. One severe form of disseminated TB is miliary TB, which can be fatal. Miliary TB arises when the bacteria spread throughout the lungs and other organs in the body.

This condition causes the development of tiny (1 to 2 mm) tubercular spots, which look similar to millet seeds – hence the name ‘miliary’. This term comes from the Latin word ‘miliarius’, which relates to the millet seed. On an X-ray, these spots, referred to as ‘miliary mottling’, are often used to help diagnose miliary TB. It’s important to note that miliary TB can affect both the lungs and other parts of the body.

For more information on the symptoms, causes, and treatment of tuberculosis, visit our companion topic “Tuberculosis” here.

What Causes Miliary Tuberculosis?

Mycobacterium tuberculosis (MTB) is a type of bacteria primarily responsible for causing tuberculosis (TB) in countries where TB from cows has been eliminated. Humans who are infected with MTB serve as a natural reservoir, meaning they can store and spread the bacteria.

MTB has certain characteristics: it does not form spores (hardened, protective shells), it does not move independently, it requires oxygen to survive, it can live both inside and outside of cells, and it doesn’t possess the enzyme called catalase. In simple terms, it’s a type of complex bacteria that has adapted to live and multiply in our bodies.

When it comes to identifying MTB, it doesn’t respond to staining methods typically used for most bacteria because it’s gram-neutral, which means it doesn’t have the type of cell wall that responds to Gram staining, a common test in bacteriology. However, it can be identified by Ziehl-Neelsen staining, a special stain used for detecting certain types of bacteria.

The cell wall of MTB contains special fatty acids called mycolic acids, which allow these bacteria to retain some stains even when washed with an acid-alcohol solution, hence they are sometimes named as acid-alcohol-fast-bacillus (AAFB).

There are other types of bacteria related to MTB. They’re classified as ‘nontuberculous’ or ‘atypical’ mycobacterial organisms because they don’t cause TB. These are frequently found in the environment, but can sometimes cause lung disease in humans.

Risk Factors and Frequency for Miliary Tuberculosis

As reported by the World Health Organization (WHO), in 2017, there were about 10 million new cases of Tuberculosis (TB) globally, and 1.3 million people lost their lives to this disease. Most of these cases came from developing countries. However, the patterns of a specific type of TB called “miliary TB” have been changing because of several factors:

• Use of medications that suppress the immune system
• People moving from countries where TB is very common
• Increasing number of HIV cases
• Alcohol abuse
• Other health issues that weaken the immune system, like diabetes and chronic kidney disease

In 2019, the United States reported 8920 new cases of TB, according to the Centers for Disease Control and Prevention. Miliary TB contributed to about 1% to 2% of these cases, and made up to 20% of all types of TB affecting parts of the body other than the lungs in people whose immune system is functioning properly.

Before the wide use of antibiotics, Miliary TB was mainly seen in infants and children. Now, however, there are two age groups where this disease is most commonly found: young adults and adolescents, and older individuals. It is also slightly more common in males.

Signs and Symptoms of Miliary Tuberculosis

Miliary TB is a form of tuberculosis that has widely varied symptoms, which often aren’t recognized until the disease is quite advanced. Its initial symptoms are usually nonspecific, such as fever, general weakness, loss of appetite, weight loss, and tiredness. Some patients may also experience coughing, difficulty breathing, chest pain, coughing up of blood, and a variety of abdominal symptoms in the early stages.

This form of TB can affect almost any part of the body, with the lymphatic system, bones, joints, liver, central nervous system, and adrenal glands being the most commonly affected. It’s possible for symptoms to appear in relation to dysfunction in these affected organs.

Miliary TB has two clinical types — classical acute and cryptic miliary TB — which have different patient profiles and symptoms. Both types need to be diagnosed and treated as early as possible.

Acute Miliary TB

People with acute miliary TB are usually under 40 years of age. Most will have a history of subacute or chronic constitutional symptoms and symptoms related to certain organs depending on which organ the disease affects. Common symptoms include fevers in the evening or night sweats for 1-2 weeks, coughing that produces little to no mucus, difficulty breathing, and sometimes coughing up of blood. Rarely, it can present as an acute respiratory distress syndrome, which is life-threatening.

Miliary TB can manifest as adrenal insufficiency (Addison disease), which is characterized by skin hyperpigmentation, low blood pressure, low blood glucose, and electrolyte imbalance.

TB can spread to the liver, intestines, and the lining of the abdominal organs leading to upper right abdominal pain, nausea, vomiting, fever, generalized fatigue, and failure to gain weight in children. TB peritonitis, which may present with fever, fatigue, and abdominal pain and swelling, may be suspected when a patient presents with such complaints.

On examination of the eye, the presence of choroid tubercles is a definitive sign of miliary TB. These are usually less than a quarter of the size of the optic disc and are located within 2 cm of the optic nerve.

It can affect the musculoskeletal system, resulting in symptoms such as back pain and tenderness, stiffness and curvature of the spine, joint pain and inflammation. Other symptoms may include bone infection, inflammation of the sheath around a tendon, inflammation of a bursa, and pus-filled muscle infection.

Potential neurological manifestations can include headaches, neck stiffness due to TB meningitis, or abnormal sensorimotor signs due to myelopathy.

Some people may experience erythematous (red or pink) macules and papules, which indicate the spread of TB in the skin.

While significant heart or kidney involvement is rare, it can lead to myocarditis, heart failure, endocarditis, aneurysms, and acute kidney injury.

Symptoms are similar in children and adults. However, in adults, common symptoms like chills, night sweats, coughing up blood, and cough with mucus are reported less often than in adults. On the other hand, peripheral lymph gland enlargement and enlargement of the liver and spleen are more common in children.

Miliary TB’s symptoms in people with HIV depend on their immune system status. Those with a stronger immune system (CD4+ count greater than 200 cells/mm) experience disease progression similar to those with a normally functioning immune system. However, those with a weaker immune system (CD4+ count less than 200 cells/mm) develop atypical symptoms such as skin lesions, swollen lymph nodes within the chest, and an abnormal response to skin tests for tuberculosis.

Cryptic Miliary TB

Cryptic miliary TB is usually seen in people over 60 years of age. It can be considered in diagnoses of unknown fevers or potentially metastatic cancer, as symptoms such as fever, progressive weight loss, and general weakness may occur without the typical symptoms of TB. However, mild enlargement of the liver and spleen may be observed. Normal chest x-rays and negative skin tests for TB often lead to delays in diagnosis.

Atypical presentations such as acute respiratory distress syndrome, pneumothorax (collapsed lung), reduced blood cell counts, septic shock, kidney inflammation related to the immune system, heart valve infection, aortic aneurysm, yellowing of the skin and eyes with blockage of bile flow, and low sodium levels due to an inappropriate release of the antidiuretic hormone can delay the diagnosis.

Testing for Miliary Tuberculosis

Diagnosing a specific form of tuberculosis, known as miliary TB, requires high-level planning and vigilance. This includes taking a careful patient history, performing physical examinations, and using radiological imaging and lab tests to make a precise diagnosis and provide suitable treatment.

Lab Tests

The blood changes often seen in miliary TB are not unique to this condition. You may see changes in your blood cell counts, or increased levels of inflammation markers such as erythrocyte sedimentation rate and C-reactive protein. Sometimes, miliary TB can be mistaken for leukemia. Other biochemistry tests may show abnormal levels of sodium, bilirubin, and calcium, among others.

Imaging Studies

The diagnosis of miliary TB doesn’t follow a one-size-fits-all approach. Instead, doctors will take into account a variety of factors like your symptoms, the images from your radiological tests, and laboratory evidence. Your doctor may order a chest x-ray or high-resolution computed tomography (HRCT) scan to look for signs of TB in your lungs. They may also suggest an ultrasound, CECT, and MRI to check other parts of the body. New techniques such as positron-emission tomographic CT are also being used.

For those with suspected TB outside of the lungs, the doctor may need to collect fluid samples from various parts of the body or take a sample of your bone marrow or liver tissue for further analysis.

Immunology-Based Methods

Skin tests that measure your body’s reaction to the TB bacteria may be ordered, but these tests are not always reliable in cases of miliary TB. Other tests like the adenosine deaminase (ADA) and interferon-γ (IFN-γ) tests can help identify TB in fluids collected from the pleural cavity (space around your lungs), pericardium (sac surrounding your heart), and abdomen.

Molecular Studies

Advanced techniques like polymerase chain reaction and Gene Xpert MTB/RIF can help in the early detection of TB and can also tell if it’s drug-resistant. These tests can use a variety of tissue samples and the results can typically be available within hours.

Definitive Diagnosis

The ultimate confirmation of TB comes from capturing and successfully growing the TB bacteria from a sample collected from the patient. This could be sputum (the substance you cough up), bodily fluids, or biopsy samples. Samples are typically grown on special agar-based media, and then analyzed for the presence of TB bacteria. The presence of TB bacteria can also be confirmed by staining techniques.

In the lab, a special kind of container with a growth indicator can reduce the detection time to 1 to 3 weeks, compared to 6 to 8 weeks for a normal growth medium. Blood cultures, on the other hand, usually don’t yield positive results except in cases where the patient’s immune system is compromised.

Finally, taking a tissue biopsy to look for granulomatous inflammation with a condition called caseation can be suggestive of TB. To truly confirm the diagnosis, the TB bacteria must be found by staining or culturing the sample.

Treatment Options for Miliary Tuberculosis

Miliary Tuberculosis (TB) is a severe form of tuberculosis that can be treated using a standard drug regimen. According to the World Health Organization, this treatment plan commonly involves a 6-month course of four different medications: isoniazid, rifampicin, pyrazinamide, and ethambutol for the first two months, followed by another four months of isoniazid and rifampicin. The duration of the treatment may vary depending on factors like the patient’s age, immune system state, and the infection’s location in the body.

In some cases, longer treatment periods may be needed. This might apply to children, individuals with weakened immune systems, patients whose condition improves slowly, and those who have Tuberculous Meningitis (TBM), TB lymphadenitis, or skeletal TB. For instance, skeletal TB typically requires treatment for at least 9 months, and TBM treatment usually lasts 12 months.

Previously, a standard treatment period of 9 months was recommended for abdominal TB. However, recent findings suggest that both 6-month and 9-month treatment plans can be equally effective.

If you have been treated for TB in the past, it’s important to have culture and drug susceptibility testing (DST) to help choose the best treatment option. In some health care settings, rapid DSTs can guide the adjustment of your regimen based on your past medical history and current condition.

Before beginning TB treatment, patients should be tested for diabetes and HIV, as these conditions may influence the treatment approach. If you have both HIV and TB, taking antiretroviral treatment for HIV in the early weeks of TB treatment may cause excessive immune reaction to TB, requiring adjustments in the medication regimen.

In addition to medical treatments, some physical interventions may be needed. For example, mechanical breathing support might be necessary for acute respiratory distress syndrome (ARDS), and surgeries could be required for diagnosing or addressing certain complications.

There’s some evidence that corticosteroids may help in specific scenarios, such as adrenal insufficiency, large accumulations of fluid around the lungs or heart, an excessive immune response (IRIS), breathing difficulties (ARDS), kidney inflammation caused by immune reaction (immune-complex nephritis), and secondary hemophagocytic syndrome. Additionally, regular monitoring of liver function may be required during TB treatment to avoid medication-induced hepatitis.

If any liver damage is detected (characterized by increased levels of certain enzymes or bilirubin), drugs potentially harmful to the liver—such as isoniazid, rifampicin, and pyrazinamide—should be discontinued to prevent further harm. Treatments may be modified and resumed once your liver function tests have normalized.

What else can Miliary Tuberculosis be?

Miliary TB, a form of tuberculosis, is known for its wide range and non-specific symptoms that often make diagnosing it difficult. Common symptoms include fever, chills, night sweats, loss of appetite, weight loss and fatigue. However, these symptoms could indicate a range of health problems, not just miliary TB. Other symptoms like headache, seizures, altered mental state, cough, chest pain, spitting up blood, stomach pain, swollen lymph nodes, an enlarged liver or spleen, back pain, and neurologic problems could all point towards various diseases. Because the symptoms of miliary TB often appear slowly and they’re not specific to the disease, it’s often difficult to diagnose it quickly. But, by considering the combination of symptoms and the patient’s demographic and immune condition, doctors can identify potential cases of miliary TB.

Many different medical conditions can cause a miliary-like pattern to appear on a chest X-ray or CT scan. So, doctors need to thoroughly examine the patient to make an accurate diagnosis. Other conditions that could cause these similar X-ray or CT scan patterns include:

• histoplasmosis (a type of fungal infection)
• blastomycosis (another fungal infection)
• coccidioidomycosis (a rare type of fungal infection)
• nocardiosis (a bacterial infection)
• sarcoidosis (an inflammatory disease)
• various forms of lung cancer
• metastatic carcinoma (cancer that has spread to secondary locations)
• infections that have spread from another part of the body
• pulmonary hemosiderosis (a lung disorder caused by excessive iron)
• hypersensitivity pneumonitis (a lung disease caused by inhaling certain substances).

What to expect with Miliary Tuberculosis

Miliary Tuberculosis (TB), a severe form of TB that spreads throughout the body, has high rates of sickness and death. The most significant cause of death seems to be a delay in treatment. On average, approximately 15-20% of children and 25-30% of adults with miliary TB do not survive due to this disease.

For patients suffering from Acute Respiratory Distress Syndrome (ARDS), a severe lung disease due to miliary TB, specific scores from a medical assessment known as the Acute Physiology and Chronic Health Evaluation (APACHE II) can predict the risk of death:

– Scores greater than 18
– Scores 18 or lower, combined with low sodium levels (hyponatremia) and a measure of oxygen in the bloodstream (the ratio of arterial oxygen tension to the fraction of inspired oxygen, or FiO2) that is 108.5 or less.

Possible Complications When Diagnosed with Miliary Tuberculosis

If miliary tuberculosis (TB) is not treated in time, several severe complications can occur, such as:

• Acute Respiratory Distress Syndrome (ARDS), a serious lung condition
• Multiple Organs Dysfunction Syndrome (MODS), a condition where many organs failure occur at once
• Tubercular empyema, infection in the lung pockets
• The air leak conditions pneumothorax and pneumomediastinum, where air collects in unneeded places
• Tubercular pericardial effusion and pericarditis, different types of severe heart disorders
• Immune reconstitution inflammatory syndrome, a reaction of the immune system
• Heart inflammation, illness in natural and artificial heart valves, and masses inside the heart
• Unhealthy enlargement of the aorta
• Tubercular meningitis with specific losses in physiological function
• Systemic amyloidosis, a disease where an abnormal protein, called amyloid, builds up in your tissues and organs
• Immune complex glomerulonephritis, a type of kidney disease
• Bone marrow suppression
• Disseminated intravascular coagulation, a condition that causes dangerous blood clotting

People who have problems with their immune system, such as those with illnesses like HIV that result in low CD4+ counts, those taking medications that suppress the immune system, and those with inborn immune conditions, may experience a rapid worsening of their condition.

Preventing Miliary Tuberculosis

Understanding tuberculosis (TB) and receiving the right advice is absolutely vital for managing the disease. Educational resources should be given to those who are at risk of contracting TB as this helps to cut down on the potential spread of the bacterial infection and increase its detection. People who have been diagnosed with TB need to be aware of key things:

They should understand how the disease operates, its related symptoms, and the importance of sticking to their Anti-tuberculus Therapy (ATT) – a treatment for TB – and regular check-ups. They also need to keep an eye out for signs of side effects from the medication and take steps to prevent the spread of Mycobacterium Tuberculosis, the bacteria that causes TB, to those close to them.

Healthcare professionals also need to keep a close watch on their TB patients, looking out for signs of the patient’s response to the treatment, any adverse drug reactions or even no response at all. This is to help personalize and optimize their treatment plan.